This research project is designed to develop relevant, cost effective rodent models for human xenotransplantation. The work outlined in the present proposal is designed to: (1) exchange cardiac xenografts between selected groups of donor/recipient species combinations and establish the immunopathologic characteristics of the type of xenograft reaction observed; (2) establish the nature of the immunoglobulin genes and B cell subsets that control the humoral response to xenografts and whether this response is consistent for different donor species; (3) compare the pattern of rejection for cardiac, liver, kidney, and pancreatic islet xenografts in a single door/recipient species combination, and (4) use rat monoclonal antibodies to isolate and characterize xenograft target antigens, first in hamster and later in related species, to establish the most appropriate species combination for providing the basis for similar experiments in species that may serve as potential xenograft donors for humans. The information derived from these studies will be important for defining which species of small animals can be considered to represent the best models for human pig and/or primate xenografting. The definition of the most appropriate rodent model for human xenotransplantation has the potential for wide use by investigators in many areas of medical research, especially those in which the use of tissues from non-human donors are used as a part of new treatment strategies for diseases such as diabetes, neurological disorders, cardiovascular disease and specific gene therapies.